Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway

Kyu Yeon Hur; Soo Hyun Kim; Min Ah Choi; Darren R. Williams; Yong ho Lee; Sang Won Kang; Umesh C.S. Yadav; Satish K. Srivastava; Mankil Jung; Jin Won Cho; Sang Geon Kim; Eun Seok Kang; Eun Jig Lee; Hyun Chul Lee

doi:10.1016/j.atherosclerosis.2010.01.035

Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway

Kyu Yeon Hur, Soo Hyun Kim, Min Ah Choi, Darren R. Williams, Yong ho Lee, Sang Won Kang, Umesh C.S. Yadav, Satish K. Srivastava, Mankil Jung, Jin Won Cho, Sang Geon Kim, Eun Seok Kang, Eun Jig Lee, Hyun Chul Lee

Department of Life Science

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2) - antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis.

Original language	English
Pages (from-to)	69-76
Number of pages	8
Journal	Atherosclerosis
Volume	211
Issue number	1
DOIs	https://doi.org/10.1016/j.atherosclerosis.2010.01.035
State	Published - Jul 2010

Bibliographical note

Funding Information:
We thank Professor Chun Sik Park for helpful discussions and critical review of the manuscript and Professor Ki-Chul Hwang (cardiovascular research institute, cardiology division, Yonsei university college of medicine, Seoul, Republic of Korea) for generous support to isolate VSMCs. This work was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A085136) and Lilly Korea.

Keywords

Diabetes mellitus
Diabetic atherosclerosis
Magnesium lithospermate B
Nrf2
Oxidative stress

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10.1016/j.atherosclerosis.2010.01.035

Cite this

Hur, K. Y., Kim, S. H., Choi, M. A., Williams, D. R., Lee, Y. H., Kang, S. W., Yadav, U. C. S., Srivastava, S. K., Jung, M., Cho, J. W., Kim, S. G., Kang, E. S., Lee, E. J., & Lee, H. C. (2010). Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. Atherosclerosis, 211(1), 69-76. https://doi.org/10.1016/j.atherosclerosis.2010.01.035

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title = "Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway",

abstract = "Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2) - antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis.",

keywords = "Diabetes mellitus, Diabetic atherosclerosis, Magnesium lithospermate B, Nrf2, Oxidative stress",

author = "Hur, {Kyu Yeon} and Kim, {Soo Hyun} and Choi, {Min Ah} and Williams, {Darren R.} and Lee, {Yong ho} and Kang, {Sang Won} and Yadav, {Umesh C.S.} and Srivastava, {Satish K.} and Mankil Jung and Cho, {Jin Won} and Kim, {Sang Geon} and Kang, {Eun Seok} and Lee, {Eun Jig} and Lee, {Hyun Chul}",

note = "Funding Information: We thank Professor Chun Sik Park for helpful discussions and critical review of the manuscript and Professor Ki-Chul Hwang (cardiovascular research institute, cardiology division, Yonsei university college of medicine, Seoul, Republic of Korea) for generous support to isolate VSMCs. This work was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A085136) and Lilly Korea. ",

year = "2010",

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doi = "10.1016/j.atherosclerosis.2010.01.035",

language = "English",

volume = "211",

pages = "69--76",

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Hur, KY, Kim, SH, Choi, MA, Williams, DR, Lee, YH, Kang, SW, Yadav, UCS, Srivastava, SK, Jung, M, Cho, JW, Kim, SG, Kang, ES, Lee, EJ & Lee, HC 2010, 'Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway', Atherosclerosis, vol. 211, no. 1, pp. 69-76. https://doi.org/10.1016/j.atherosclerosis.2010.01.035

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T1 - Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway

AU - Hur, Kyu Yeon

AU - Kim, Soo Hyun

AU - Choi, Min Ah

AU - Williams, Darren R.

AU - Lee, Yong ho

AU - Kang, Sang Won

AU - Yadav, Umesh C.S.

AU - Srivastava, Satish K.

AU - Jung, Mankil

AU - Cho, Jin Won

AU - Kim, Sang Geon

AU - Kang, Eun Seok

AU - Lee, Eun Jig

AU - Lee, Hyun Chul

N1 - Funding Information: We thank Professor Chun Sik Park for helpful discussions and critical review of the manuscript and Professor Ki-Chul Hwang (cardiovascular research institute, cardiology division, Yonsei university college of medicine, Seoul, Republic of Korea) for generous support to isolate VSMCs. This work was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A085136) and Lilly Korea.

PY - 2010/7

Y1 - 2010/7

N2 - Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2) - antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis.

AB - Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2) - antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis.

KW - Diabetes mellitus

KW - Diabetic atherosclerosis

KW - Magnesium lithospermate B

KW - Nrf2

KW - Oxidative stress

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DO - 10.1016/j.atherosclerosis.2010.01.035

M3 - Article

C2 - 20172524

AN - SCOPUS:77954314390

SN - 0021-9150

VL - 211

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JO - Atherosclerosis

JF - Atherosclerosis

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ER -

Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway

Abstract

Bibliographical note

Keywords

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